Management of Candiduria: Grey Zones Still Exist

Candida species cause a wide spectrum of diseases, of
which the prevalence of candiduria varies considerably between nosocomial
settings, being most prevalent among patients admitted to the intensive care
unit (ICU). However, lacking management and treatment guidelines and the
existence of dilemmas have inhibited efforts to curtail cases of candiduria for
this vulnerable population.

Critically
ill patients are a susceptible group for opportunistic Candida infections. The major
risk factors identified with candiduria are extremes of age, female sex,
diabetes mellitus, use of immunosuppressive agents, interruption of the flow of
urine, radiation therapy, and so on. However, in nosocomial settings, the major
risk factors are the use of urinary catheters and the prior use of
broad-spectrum antimicrobial agents (Passos et al. 2005).

Presently,
the incidence of candiduria in the ICU population ranges from 19% to 44% of
urine specimens, depending upon the patient cohort and the definition of
candiduria (Toya et al. 2007). The causative species of candiduria vary in
different studies. Candidaalbicans is responsible for at
least 50% of all cases of fungiuria, followed by Candida glabrata (15.6%), Candidatropicalis (7.9%), Candida parapsilosis (4.1%), and Candidakrusei (1%) (Kauffman et al.
2000). C. glabrata most often is isolated from individuals who have been treated with
fluconazole, while C. parapsilosis is seen most frequently in neonates. It is noteworthy that for
approximately 10% of patients with candiduria, at least two types of Candida species are isolated
from the same urine culture. Candiduria frequently coexists with or follows
bacteriuria.

Treatment Dilemmas

The major problem with candiduria is in determining its practical
importance. The condition can arise as a result of contamination, colonisation
or a true urinary tract infection. Due to lack of a reliable method for
differentiating colonisation from infection, the condition is a dilemma for the
clinician from the treatment point of view. Frequently it has been reported to
be the first sign of disseminated disease or candidaemia. After adjusting the
various covariates, the overall ICU mortality rate among patients with
candiduria has been found to reach 20-50% (Hollenbach 2008). Therefore, if neglected, it can evidently be detrimental for the
patient. As a result, even if the decision is not to treat the patient, the
clinician has to be vigilant. In the case of isolation of C. albicans, the possibility of
colonisation should be kept higher than true infection as it is a part of
normal flora, especially in female patients. However, if non-albicans Candida are
isolated, it is advisable to determine whether it is really colonisation. There
is also need to perform surveillance cultures at various body sites of the same
patient to determine the colonisation index.

As far as the question of when
to start the treatment cutoff is concerned, there are no clear-cut guidelines.
The decision lies upon the clinical acumen of the attending physician.
Asymptomatic candiduria is usually expected to resolve within weeks to months
without therapeutic intervention in the vast majority of individuals. Treatment
is warranted only in certain patient populations, such as those at risk for
developing a disseminated fungal infection. These include neutropenic or
oncology patients, patients with sepsis, infants with low birth weight,
neonates, those with a known urologic obstruction and those likely to undergo
urologic manipulations (Lundstrom et al. 2008). In cases of asymptomatic
candiduria in outpatients or other predisposed inpatients, the best method is
to get rid of predisposing conditions. However,
in ICU patients, it may not be possible to remove the catheter permanently,
stop the ongoing antibiotic therapy or make the patient undergo surgery for
predisposing urologic abnormality immediately. In such conditions, careful
monitoring is required. The patient’s urine cultures should repeatedly be
tested for Candida so that if presence is detected the possibility of contamination can
be ruled out. The Microbiology laboratories cannot help much in differentiating
colonisation from infection on their own. The cutoff value for candiduria that
indicates presence of infection varies from 103 to 105 colony-forming units
(CFUs) The problem of multiple species in the same sample, and cutoff criteria
for cases of non-albicans Candida species isolation, are still to be addressed. There have been some
attempts to distinguish infection from colonisation of the bladder by looking
for the presence of pseudohyphae or antibody-coated yeasts in the urine.
However, species such as C. Glabrata do not produce pseudohyphae, and C.
albicans can be induced to form pseudohyphae by varying
the pH and nutrients in the urine. Detection of antibody-coated yeast has also
been shown to be non-specific (Hollenbach, 2008).

For
the symptomatic conditions like pyelonephritis and fungus ball, clear-cut
treatment guidelines have already been defined (Pappas et al. 2009). Even in
cystitis, the patient is usually symptomatic and fluconazole is given as a
first line of treatment. In cases of fluconazole resistant species, the
treatment is amphotericin B (deoxycholate, as liposomal amphotericin B achieves
low concentration in renal tissue) or flucytosine. However, fluconazole use is
limited in the context of advanced renal failure and infections with non-albicans species, most notably C. glabrata. Echinocandins are
usually recommended in invasive or disseminated candidiasis, but in renal
involvement their efficacy is not proven, due to their poor urinary
bioavailability. Some authors have found that candiduria was eradicated in
their patients after parenteral caspofungin therapy was given (Sobel et al. 2007).
Parenteral caspofungin achieved high renal tissue concentrations independent of
glomerular filtration. Currently, IDSA guidelines do not recommend
echinocandins for treatment of candiduria because of very limited clinical
data. The feasibility of caspofungin administration via a nephrostomy tube also
needs to be determined. It is still to be seen whether the potent activity of
caspofungin against C. glabrata (a frequent uropathogen) and other non albicans Candida can be
exploited or not (Sobel et al. 2007).

Last but not the least, the presence of yeast cells in urine is
labelled as candiduria traditionally; but now many new fungi like Trichosporon species are
emerging as frequent isolates in urine samples of hospitalized patients (Singla
et al. 2012). The existing data also reveals a profile of high resistance of
the genus Trichosporon to amphotericin B and itraconazole with moderate resistance to 5-
flucytosine (Sun et al. 2012).

Management and Guidance

Due to increasing Candida infections, an increase in non-albicans Candida and other yeast, increasingly compromised immune systems
increasing predisposition to Candida
and Candida establishing
itself at position four in the isolation list from bloodstream infections, we
can no longer neglect Candida's isolation from body sites, even from a urine sample.
There is a need to establish a Candida surveillance programme for all ICU
patients and to follow-up patients with candiduria even after their discharge
from an intensive care facility, to generate authentic data regarding its
pathogenicity. Guidelines available do not dwell much on cutoff definitions and
culture techniques to be employed. Various studies have kept their own criteria
for analysis of candiduria. Some studies even show
gender bias (Achkar et al. 2010). This variability and unreliability in
laboratory procedures skews the analysis of the incidence and outcome of
candiduria. Most of the studies have concentrated on epidemiology and risk
factor evaluation, but it is also important to have data on recurrences and
relapses, with uniform definitions for these terms, after treatment has been
given. Candida,
being a master in opportunism, exhibits strain microevolution and genetic
variability. This fact has been supported in cases of candidaemia (Toya et al.
2007). Similar reasons could be there for persistence and relapse in cases of
candiduria too. Lack of consensus and the availability of limited literature
are the main reasons that we cannot formulate the proper guidelines. For the
time being, the approach to candiduria remains individualised and proper
assessment of the patient’s risk factors is the key to treatment.

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